One of the areas of neurobiology that has received considerable attention concerns the underlying causes of the variability in transmitter release and facilitation exhibited by different synapases in response to the temporal sequence of nerve impulses. The nature of these causes is as yet unknown, but recent work has been concerned with two avenues of investigation: the role of nerve terminal activity and the role of calcium influx or mobilization. This problem will be investigated in a crustacean neuromuscular system which exhibits considerable synaptic diversity and which will serve as a model for synaptic mechanisms in the CNS of vertebrates. The distal accessory flexor muscle of the lobster (Homarus americanus) is composed of approximately 20 fibers multi-terminally innervated by a single excitatory motor axon. The synapses arising from this lone axon vary in the amounts of transmitter released at different stimulation frequencies. The extremes of this range, i.e., low-output, highly facilitating and high-output, poorly facilitating types, are regionally distributed on proximally- and distally-located fibers respectively, and thus each synaptic type is uniquely identifiable. Parallel ultrastructural studies have shown that quantal transmitter output is correlated with size of presynaptic paramembranous dense bodies which thus presumably represent active release sites. These results will be extended further using electrophysiological, ultrastructural and pharmacological techniques. In particular we will attempt to determine: 1) differences in progressive spike invasion and nerve terminal membrane excitability at the diverse synaptic types: 2) the dependence of transmitter release and facilitation on internal and external calcium concentrations; 3) the ultrastructural correlates of transmitter release particularly in regard to facilitation and pharmacological alterations of calcium fluxes, and finally, the statistical parameters of transmitter release associated with the above procedures.